SUMMARY While children can contract SARS-cov-2, they usually develop a milder form of the disease than adults. A common explanation is that their immune system is more robust than that of adults. Based on our previous research on B cell immunity in human neonates, we hypothesize that innate humoral immunity present at birth, and dwindling with age, confer a first line of defense against SARS-CoV-2, attenuating the severity of the disease. Our studies will test for the presence of natural IgM, IgG and IgA reactive to major components of the virus (spike, nucleocapsid?) in neonates and adults. Moreover, we have already generated >300 recombinant monoclonal antibodies (mabs) from plasma cells isolated from neonatal thymus specimens. We will test the antiviral activity of these mabs. If successful, our studies will uncover a critical immune component responsible for children?s apparent resistance to SARS-cov-2. We will also identify specific mabs with therapeutic potential. Aim 1. To assess natural serological immunity to SARS-CoV-2 Studies in aim 1 will test for the presence of IgM, IgG and IgA reactive to SARS-cov-2 proteins in the serum of neonates and healthy adults as controls. Experimentally, we will use plasma and serum samples collected before the start of the COVID-19 pandemic. Our repository already includes 48 cord blood specimens and 35 healthy adult blood specimens as controls. As a source of antigens, we will first use commercially available recombinant viral proteins. We will also test the reactivity of cord blood antibodies to viral proteins expressed in primary human airway epithelial cells. Aim 2. To identify recombinant monoclonal antibodies with therapeutic potential As part of our ongoing study on the development of humoral immunity in human neonates (U01-AI-131339), we have generated 362 recombinant monoclonal antibodies (mabs) from plasma cells isolated from 5 neonatal thymus specimens. These mabs are a representative sample of the natural antibody repertoire of neonates. Experiments in aim 2 will assess the reactivity of these mabs to SARS-CoV-2 antigens. All reactive mabs will be further characterized for their reactivity profile, sequence and capacity to neutralize SARS-CoV-2 infectivity.